A pilot study of ipilimumab and nivolumab in recurrent extensive-stage small cell lung cancer after platinum-based chemotherapy.
Authors: Anne C. Chiang, Matthew Austin, Tyler F. Stewart, Mohammad Arammash, Sunil Bhatt, Scott N. Gettinger, Sarah B. Goldberg, Frederick Hugh Wilson, Benjamin Robert Newton, Michael Keith Cohenuram, Kert D. Sabbath, Ashita D. Talsania, Armand Vincent Russo, Roy S. Herbst, Kurt A. Schalper
Journal: Journal of Clinical Oncology (2022)

8583 Background: Immunotherapy has shown efficacy in the treatment of recurrent, extensive-stage small cell lung cancer (ES-SCLC). In the Checkmate 032 trial, ipilimumab and nivolumab combination therapy resulted in a 21% objective response rate in relapsed SCLC. At present, there are no biomarkers used in clinical practice to predict treatment responsiveness in SCLC. Ipilimumab and nivolumab act by blocking key co-inhibitory immune pathways of CTLA-4 and PD-1/PD-L1, respectively, leading to reinvigoration of anti-tumor cytotoxic T cell responses and a decrease in immune suppressive tumor infiltrating leukocytes. The ratio of intratumor Teff (CD8+) cells to Treg (CD4+/Foxp3+) cells (Teff/Treg) could be a more reliable biomarker than effector cell infiltration alone. Methods: In this open-label, single arm trial, we enrolled patients with ES-SCLC who previously received platinum-based chemotherapy; prior anti-PD-1 /PD-L1 therapy was allowed. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, for a total of 4 doses each and received nivolumab 480 mg beginning with cycle 5, every 4 weeks until progression, unacceptable toxicity or study discontinuation. On-study biopsies were performed prior to initiation of therapy and during week 4 for the biomarker primary objective—to correlate disease response with intratumor Teff/Treg changes. Secondary objectives include determining ORR, DOR, PFS, and OS. Results: Twenty-two patients (median age 63.5 [range 54-80] years, ECOG 0/1/2 [41%/50%/9%], sex M/F [45%/55%]) were enrolled and received treatment. Fourteen (64%) had paired biopsies while on treatment. Fifteen patients were evaluable per RECIST with an ORR of 13% (2/15, 2 partial responses [13%]) and DCR was 40% (6/15, 4 stable disease [27%]). Grade 3 treatment-related adverse events (TRAEs) occurred in 9/22 [40%]. Grade 4 TRAEs occurred in 2/22 [9%] (elevated lipase and elevated bilirubin) and Grade 5 TRAEs occurred in 1/22 patients (hepatic failure). Out of the 9 patients previously treated with anti- PD-1/PD-L1 therapy, 1 had a partial response and 2 had stable disease. Multiplexed quantitative immunofluorescence analysis revealed changes of both CD8+ effector T cells and Tregs in the tumor micro-environment associated with clinical benefit to immunotherapy. Conclusions: Combination immunotherapy with ipilimumab and nivolumab shows clinical efficacy in relapsed extensive-stage SCLC, including those previously treated with anti-PD-1/PDL-1 therapy. Obtaining paired biopsies was shown to be successful in this prospective trial to study the tumor microenvironment in SCLC tumors treated with checkpoint inhibitors. Early biomarker evaluation during week 4 shows local immunomodulatory effect of treatment and supports exploration as predictive biomarker in this population. Clinical trial information: 03670056.